Dr. Stephanie Graff: Understanding Progression
Episode Notes
In the inverted language of MBC, “unremarkable” is something we all aspire to, and “progression” is something we dread. Progression means that our current medication regimen is no longer working and cancer is spreading and/or growing. It means that treatment is likely to change—bringing new drugs with new side effects. It also means that we’ve exhausted one of the available treatment options for our disease, leaving fewer remaining lines of treatment. In this episode, breast oncologist Dr. Stephanie Lynn Graff helps us unravel the mysteries of progression and resistance, tissue and liquid biopsies, tumor markers and scans.
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Receptors are molecules that live on the surface of a cancer cell that can be filled (and attract) by a specific ligand, or put another way receptors are proteins or glycoprotein that bind signaling molecules known as first messengers, or ligands. They can initiate a signaling cascade, or chemical response, that induces cell growth, division, and death or opens membrane channels.
This ligand can also colloquially be called “fuel” since when the receptors are filled, that allows the cancer cell to continue to proliferate and take over more healthy cells. If you are interested in learning more about receptors
When a ligand binds to its respective receptor, the shape and/or activity of the ligand is altered to initiate several different types of cellular responses.
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Cellular receptors are proteins either inside a cell or on its surface, which receive a signal. In normal physiology, this is a chemical signal where a protein-ligand binds a protein receptor. The ligand is a chemical messenger released by one cell to signal either itself or a different cell.
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Receptors are a special class of proteins that function by binding a specific ligand molecule. When a ligand binds to its receptor, the receptor can change conformation, transmitting a signal into the cell. In some cases the receptors will remain on the surface of the cell and the ligand will eventually diffuse awa
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Like most, enzyme-linked receptors are transmembrane proteins but they are unique because in addition to receiving signals from chemical messengers they also function as enzymes. Binding of a signaling molecule activates the receptor's enzymatic activity
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Tyrosine kinases are a family of enzymes, which catalyzes phosphorylation of select tyrosine residues in target proteins, using ATP.
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Receptor tyrosine-protein kinase erbB-2, also known as CD340 (cluster of differentiation 340), proto-oncogene Neu, Erbb2 (rodent), or ERBB2 (human), is a protein that in humans is encoded by the ERBB2 gene.
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The main difference between enzyme and protein is that the enzyme is a biological catalyst whereas the protein can involve in the formation of structures, transportation, catalysis, and regulation of biological processes.
Enzymes and proteins are intrinsically linked and often confused. Essentially, an enzyme is a specific type of protein that performs a very specific function. Enzymes function to regulate biochemical reactions in living things, in this sense, they operate solely as a functional protein, while a protein can be either functional or structural. Therefore, all enzymes can be adequately described as globular proteins, however, not all proteins are globular. Proteins are macromolecules, that consist of polymers of amino acids that come to operate as the structural and functional basis for cells within living things. A protein can have multiple functions, including but not limited to enzyme catalysis, defense, transport, storage, and support.
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For breast cancer, there are three (3) different receptors that are typically used to describe a subtype and which are often targeted for treatment. They are:
1) Estrogen;
2) Progesterone; and
3) Her2 neu.
For the first two receptors, both hormones made naturally by the body, a pathology report will include a percentage of positivity.
For the last receptor, the pathology reports typically just include positive or negative; however, there is some new data/studies looking at a third category of Her2-low, which opens up some additional treatment options
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From the interview transcript: “
I am going to use HER2 as an example.
Remember, at the very beginning of your breast cancer diagnosis, you were probably told that your HER2 was HER2 0, 1+, 2+, or 3+. That means that when we look at your cancer under the microscope and literally dump ink on cells, that's how much ink sticks to your cancer under the microscope. What the ink is sticking to is the HER2 receptors. And the more ink that sticks, the more receptors are on the surface of the cell. And so somebody who has 1+ has more receptors than somebody who is HER2 0 and somebody who has her 2+ has more than somebody who has 1+.
Our definition of positive is 3+. For somebody who's 2+, we typically do the FISH test to look to see if they're amplified, because you can have a medium number of receptors and still have that gene turned on in the cell.
But we know that a lot of breast cancer will have HER2 on the surface. That's why now we're seeing trastuzumab deruxtecan being tested and this new concept. of HER2 low breast cancer
People who are her2 zero, it's not that they don't have any of HEr2, it's that there's not much ink sticking to that cancer cell. So when cancers develop resistance. Interestingly, one of the mechanisms of estrogen resistance is to up-regulate HER2, because there's some crosstalk in the cell.
And so by making more, HER2 on the surface, it can help bypass that estrogen blockade, even if HR2 isn't your cancer's thing. So even if you are HER2 negative, your breast cancer can use HER2 to get around estrogen.
Up-regulation just means that your cancer cell decides to sprout more of that particular pattern on the surface of cancer cells.
Down-regulation is the opposite of that process. Down-regulation is the mechanism that estrogen typically uses. And we see that a lot in tumors. They down-regulate the progesterone receptors. So we see somebody who has ER 95% PR 95% on the future biopsies become ER 80% PR 40%.
Their cancer starts to turn down how much estrogen and progesterone is being expressed, and that's a way it's developing resistance.
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A tumor marker is a biomarker found in blood, urine and body tissue. It could be produced by the tumor itself or by the body's response to the tumor. In breast cancer, there are tumor markers in the blood that your doctor may measure serially. Serial measurements show how the level of a marker changes over time. In some people, a decrease in the level of a specific marker may mean the tumor is responding to treatment while an increase could mean the opposite. The usefulness of the information these tumor markers provide depends on various factors, including the subtype of breast cancer.
They may have less usefulness in HER2 positive and TNBC subtypes and the individual patient. The most frequent serial measured tumor markers in the blood for breast cancer are
1. CEA Which is a marker that's often used for colorectal cancer, but it can be useful in monitoring treatment response in breast cancer, too
2. CA 15-3 and CA 27-29 CA stands for Cancer Antigen are related tumor markers that are made by breast cancer cells. So finding them in the blood, it can signal breast cancer or lack of treatment effectiveness.
3. CA-125 is associated with both ovarian cancer and breast cancer
Tumor markers like these can be elevated for reasons, unrelated to breast cancer, such as another type of cancer or benign condition.
They are one of the tools our doctors can use to see what is happening, but on their own, they aren't sufficient to monitor for progression or treatment effectiveness.
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Liquid biopsy is the use of a patient fluid sample rather than a tissue sample for the same kind of clinical utility one would get from a traditional biopsy. It has been shown that during tumor progression, the tumor can shed a few biomarkers into the bloodstream, including cells, proteins, and nucleic acids. These are linearly related to the size of the tumor and can provide a snapshot in time of the tumor status due to short biomarker half-life.
Some of the most commonly used biomarkers for liquid biopsy are circulating tumor cells (CTCs). CTCs are whole cells that shed off of the tumor and can be captured in a simple blood draw It has been shown that the concentration of CTCs correlates with disease severity, and that the surface receptors and molecular contents of the CTC are reflective of the tumor One of the major challenges with CTC capture and detection is that they are extremely rare, with typically fewer than 10 CTCs in a standard blood draw, making their separation from background blood components a challenge Once captured, CTCs can provide a wealth of information about the tumor, including an understanding of surface antigens and genetic profiling.
Another biomarker of interest is circulating tumor DNA (ctDNA). ctDNA is DNA that sheds out of the tumor through secretion, apoptosis, or necrosis It is widely believed that ctDNA can be detected sooner than other circulating biomarkers due to its larger fragment number in the blood ctDNA poses a challenge for capture and detection because it is relatively small and low in concentration. One of the biggest challenges with ctDNA capture and analysis is differentiating tumor DNA from healthy cell DNA. This requires that the technology can distinguish relatively low concentrations of mutant ctDNA in a wild type background.
The liquid biopsy represents in a more exhaustive way than the tissue biopsy the molecular heterogeneity of the disease containing, at least potentially, tumor DNA deriving from the different areas of the same tumor and possible disease locations. Moreover, the liquid biopsy can be repeated over time to monitor the molecular evolution of the disease, although there is no evidence to date to change the therapeutic choice, in the absence of clinical progression.
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Response evaluation criteria in solid tumors or RECIST is the gold standard to evaluate treatment response by using a standard measurement to evaluate the changes in the dimensions of a metastatic leasion. By using these rules, clinicians can determine when patients improve, stay the same or stable, or worsen on a treatment.
The RECIST criteria have gained widespread adoption and a widely used in oncology clinical trials. But there lies the problem. They're based on the anatomic measurement of solid tumors. . Bone metastases are typically difficult to measure with rulers
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Bone metastasis are classified as blastic, lytic, and sclerotic, and they can even be mixed. Blastic lesions fill the bone with extra cells, whereas lytic lesions destroy those cells. When we see sclerotic lesion on our scans, it's typically talking about hardening of the bone in response to treatment representing healing.
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NCCN stands for National Comprehensive Cancer Network. It's a set of guidelines that are updated periodically and accepted widely. They're used to guide providers to consider best practice treatment options. When planning a treatment regimen, practitioners will keep the guidelines into consideration, but we'll also review the most recent advances as well as patient circumstances to come up with an individualized plan.
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Traditional PET scans rely on a glucose based imaging agent that is taken up by cancer cells to diagnose metastatic sites and disease activity Syriana, which is also. F-18, Flouroestrodiol or FES for short. is a new type of PET scan that uses a contrast agent that binds to the estrogen receptor on cancers.
So only the cells that are positive for estrogen receptor will light up on the FES scan your doctor can see if you are all ER positive, partially ER positive or not at all, which will guide treatment decisions. If the FES scan shows that all metastatic sites seen on PET pet scan are also lighting up as ER positive, typo might not need to do a tissue biopsy because you'd be a candidate for estrogen blockade therapies. If however, the metastatic sites seen on PET scan do not then show up as ER positive on the FES scan, a tissue biopsy is needed to determine the molecular makeup. So. It's typically the next step to inform the best treatment for your disease.
Additional resources
Landscape of HER2-low metastatic breast cancer (MBC): results from the Austrian AGMT_MBC-Registry,Breast Cancer Research volume 23, Article number: 112 (2021)
Androgen Receptor in Breast Cancer—Clinical and Preclinical Research Insights Molecules 2020 Jan; 25(2)
ESMO Clinical Practice Guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer☆ - Annals of Oncology (from the European Society of Medical Oncologists -not an easy read but contains info on treatment options when progression occurs)
Treatment of Stage IV (Metastatic) Breast Cancer (from American Cancer Society –overview of various lines of treatment for different cancer types)
NCCN Guidelines for Patients Metastatic Breast Cancer (from the National Comprehensive Cancer Network – a truly comprehensive overview that includes info on scans and tests as well as treatment options that may be helpful to inform decisions at various points in disease progression)
Resources to seek emotional support after progression
Dealing With Cancer Recurrence
More Information
American Cancer Society: Understanding Recurrence
National Cancer Institute: Managing Cancer as a Chronic Condition
Abigail Johnston’s Blog Articles used in this episode
Blog No Half Measures LIVING OUT LOUD
Dr. Graff’s Video Appearances, Interviews, and Articles
Stephanie Graff, MD: Information Is Power for Patients With Breast Cancer, OncLive on Air, January 1, 2020
Dr. Graff on Future Research With Immunotherapy in Breast Cancer , OncLive
Dr Graff discusses future research with immunotherapy in Estrogen receptor–positive breast cancer.
Dr. Graff on the FDA Approval of Sacituzumab Govitecan in TNBC By Stephanie Graff | OncLive
Dr. Graff discusses the FDA approval of sacituzumab govitecan-hziy (Trodelvy) in metastatic triple-negative breast cancer (TNBC).
Dr. Graff on Current Treatments in ESR1-Mutant Breast Cancer By Stephanie Graff | OncLive
Dr. Graff discusses current treatments in ESR1-mutant breast cancer.
Dr. Graff Underscores Unmet Needs in By Stephanie Graff | OncLive
Dr Graff discusses some unmet needs of patients with ESR1-mutated metastatic breast cancer.
Critical Aspects of a Sustainable Clinical Research Program in the Community-Based Oncology Practice By Jennifer L. Ersek, Stephanie Graff, Neelima Denduluri, Francis P. Arena | ascopubs.org
Exemplary clinical trial sites should seek to enroll at least 10% of their patients on clinical trials. Achieving this goal requires commitment across physician and administrative leadership to create a culture of clinical research. Leaders of community-based clinical research programs must understand the patient population they serve and advocate for their patients to be involved in research.
The most valuable lessons in life can be learned in oncology By Stephanie Graff | KevinMD.com
I am a medical oncologist specializing in breast cancer. I often try to conceal what I do for a living when I meet people for the first time as it always leads down a particular road. “Is that so depressing? I don’t know how to deal with that all day, every day.” But in truth, it is not depressing. My work is very rewarding. I feel that the most valuable lessons I have learned in life, I have learned in the practice of oncology. 1. Labels hurt.
Scared of clinical trials? 7 reasons to not be.By Stephanie Graff | KevinMD.com
I see more and more patients decline to participate in clinical trials. Simultaneously, I hear patient advocates on the national stage clamoring for better trial access. Why the disconnect? Let’s explore 7 reasons why clinical trial participation is right for you:1. The smartest minds in medicine designed this for you. Clinical trials are not designed by one doctor on the fly. Most oncology drugs have been studied for at least six years prior to entering clinical trial.
Where physician and mother meet By Stephanie Graff | KevinMD.com
In 2017, results of a study were published in JAMA suggesting women are better doctors than men. While I celebrated the acknowledgment for myself and my female physician peers, it prompted me to reflect on how my gender impacts how I practice medicine. Reflection kept bringing me back to a simple truth: my job as a mother and my job as a physician are strikingly similar. They are yin and yang, balancing and strengthening me. I am constantly swinging from high to low.
The only perfect cancer statistic is an imperfect one By Stephanie Graff | KevinMD.com
As an oncologist, I spend my days with women and men diagnosed with cancer. My patients, particularly my advanced-stage or Stage 4 (metastatic) patients, often ask what they did wrong. How did they end up with metastatic cancer? They share with me the subtle accusations made by friends, family and acquaintances that somehow they brought this on themselves. “If only Susan had done her screening mammograms faithfully, she never would be in this position.” “Did you hear Bob has metastatic melanoma?
Honor National Women Physicians Day With Self-Care , Women in Oncolog, Feb 01, 201
Want more?
Check out our past episodes that deal with some of these topics.
Meet the Guest of this Episode
Stephanie Lynn Graff, MD, FACP
Dr. Graff is the Director of Breast Oncology at Lifespan Cancer Institute at the Legorreta Cancer Center at Brown University in Providence, Rhode Island.
Dr. Graff serves as co-lead of the Breast Cancer Translational Research Disease Working Group at Brown University and is an Assistant Professor of Medicine at the Warren-Alpert School of Medicine. In Dr. Graff is a medical advisor to the Dr. Susan Love Foundation for Breast Cancer Research.
Dr. Graff is board certified in Medical Oncology, Hematology, and Internal Medicine; and completed a breast oncology sub-fellowship at the University of Kansas. Dr. Graff is a PI on numerous clinical trials in addition to her work in translational research, genomics, and gender bias.
She is an award-winning writer, social media influencer, and sought-after public speaker. Dr. Graff has received the Frist Humanitarian Award for her work in the community and the Benjamin L. Sapers Memorial Award for her “passion for pedagogy, academic rigor, empathy and humanism, with profound feeling for the person as patient.”
Ultimately, Dr. Graff is passionate about connecting with her patients to provide personalized, comprehensive oncology care, advancing breast cancer research, and breast cancer prevention.
PI(3)King the right target after CDK4/6 inhibitors fail patients is an exciting area of research and FDA approval. Now that there are multiple options approved by the FDA and more to come, patients have more treatment choices. Join host Abigail Johnston as she interviews 2 patients who give us their perspective on these advances, as well as a doctor whose scientific research has led the way identifying PIK3CA mutations as a cancer genomic biomarker.